Aminoalkyl substituted 9H-pyridino[2,3-b] indole and 9H-pyrimidino[4,5-b]   indole derivatives

ABSTRACT

Disclosed are compounds of the formula: ##STR1## wherein Ar, R 1 , W and X are substituents as defined herein, which compounds are (1) antagonists at CRF 1  receptors and are, therefore, useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety; and (2) are neuropeptide Y 1  receptor antagonists, and are therefore useful in the treatment of a variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.

This is a continuation-in-part of application Ser. No. 60/080,451, filedApr. 2, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to aminoalkyl substituted9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivativeswhich selectively bind to corticotropin-releasing factor (CRF₁)receptors and to mammalian neuropeptide Y (NPY₁) receptors. It furtherrelates to pharmaceutical compositions containing such compounds and theuse of such compounds in treating physiological disorders induced orfacilitated by CRF or those associated with an excess of neuropeptide Y.

2. Description of the Related Art

Corticotropin releasing factor (herein referred to as CRF), a 41 aminoacid peptide, is the primary physiological regulator ofproopiomelanocortin (POMC) derived peptide secretion from the anteriorpituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851(1983); W. Vale et al., Science 213:1394 (1981)]. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse of the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system [for reviewsee E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Bankiet al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol.Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989).Furthermore, the density of CRF receptors is significantly decreased inthe frontal cortex of suicide victims, consistent with a hypersecretionof CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. Inaddition, there is a blunted adrenocorticotropin (ACTH) response to CRF(i.v. administered) observed in depressed patients [P. W. Gold et al.,Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng. J.Med. 314:1129 (1986)]. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. Thereis preliminary evidence that tricyclic antidepressants can alter CRFlevels and thus modulate the numbers of CRF receptors in brain[Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology ofanxiety-related disorders. CRF produces anxiogenic effects in animalsand interactions between benzodiazepine/non-benzodiazepine anxiolyticsand CRF have been demonstrated in a variety of behavioral anxiety models[D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using theputative CRF receptor antagonist α-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrate that the antagonist produces"anxiolytic-like" effects that are qualitatively similar to thebenzodiazepines [C. W Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrineand receptor binding studies have all demonstrated interactions betweenCRF and benzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the"anxiogenic" effects of CRF in both the conflict test [K. T. Britton etal., Psychopharmacology 86:170 (1985); K. T. Britton et al.,Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. Thebenzodiazepine receptor antagonist (Ro 15-1788), which was withoutbehavioral activity alone in the operant conflict test, reversed theeffects of CRF in a dose-dependent manner while the benzodiazepineinverse agonist (FG 7142) enhanced the actions of CRF [K. T. Britton etal., Psychopharmacology 94:306 (1988)].

It has been further postulated that CRF has a role in immunological,cardiovascular or heart-related diseases such as hypertension,tachycardia and congestive heart failure, stroke and osteoporosis. CRFhas also been implicated in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity associated with psychopathological disturbance andstress.

The mechanisms and sites of action through which the standardanxiolytics and antidepressants produce their therapeutic effects remainto be elucidated. It has been hypothesized however, that they areinvolved in the suppression of the CRF hypersecretion that is observedin these disorders. Of particular interest is that preliminary studiesexamining the effects of a CRF receptor antagonist (α-helical CRF ₉₋₄₁)in a variety of behavioral paradigms have demonstrated that the CRFantagonist produces "anxiolytic-like" effects qualitatively similar tothe benzodiazepines [for review see G. F. Koob and K. T. Britton, In:Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B Nemeroff eds., CRC Press p221(1990)].

Neuropeptide Y, a peptide first isolated in 1982, is widely distributedin the central and peripheral neurons and is responsible for a multitudeof biological effects in the brain and the periphery. Various animalstudies have shown that activation of neuropeptide NPY₁ receptors isrelated to vasoconstriction, Wahlestedt et al., Regul. Peptides, 13:307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. 261:863-868 (1992), and Grundemar et al., Br. J. Pharmacol. 105: 45-50(1992); and to stimulation of consummatory behavior, Flood and Morley,Peptides, 10: 963-966 (1989), Leibowitz and Alexander, Peptides, 12:1251-1260 (1991), and Stanley et al., Peptides, 13: 581-587 (1992).Grundemar and Hakanson, TiPS, 15: 153-159 (1994), state that, inanimals, neuropeptide Y is a powerful stimuli of food intake, and aninducer of vasoconstriction leading to hypertension. They further pointout that low levels of neuropeptide Y is associated with loss ofappetite. These reports clearly indicate that compounds that inhibit theactivity of this protein will reduce hypertension and appetite inanimals.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withCRF₁ receptors and NPY₁ receptors. It further relates to the use of suchcompounds, pharmaceutical compositions comprising these compounds, andmethods useful for the treatment of psychiatric and affective disordersand neurological diseases, including major depression, headaches,anxiety-related disorders, post-traumatic stress disorder, supranuclearpalsy, as well as treatment of immunological, cardiovascular orheart-related diseases, hypertension, feeding disorders, diabetes,dislipidemia, colonic hypersensitivity associated withpsychopathological disturbance, and stress. It further relates to theuse of such compounds in treating physiological disorders induced orfacilitated by CRF or those associated with an excess of neuropeptide Y.In particular, this invention provides aminoalkyl substituted9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives ofFormula I which selectively bind to corticotropin-releasing factor(CRF₁) receptors and/or to mammalian neuropeptide Y (NPY₁) receptors.

Accordingly, a broad embodiment of the invention is directed to acompound of Formula I: ##STR2## wherein Ar is phenyl, 1- or 2-naphthyl,2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, ortri-substituted with halogen, trifluoromethyl, hydroxy, amino, loweralkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido,N,N-lower dialkyl carboxamido, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, with theproviso that at least one of the positions ortho or para to the point ofattachment of Ar to the tricyclic ring system is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, C₁ -C₆ alkyl, or (C₁ -C₆alkyl)-G¹ --R² where G¹ is oxygen or sulfur and R₂ is hydrogen or C₁ -C₆alkyl;

W is N or C--R³ where R³ is hydrogen or C₁ -C₆ alkyl; and

X is ##STR3## wherein V¹ and V² are CH₂, CO, CS, SO₂ or CH(C₁ -C₆alkyl), with the proviso that both V¹ and V² cannot both be CO, CS orSO₂ ;

Y¹ and Y² independently represent a bond or C₁ -C₆ alkylene;

A¹ is NR⁴ R⁵ wherein R⁴ and R⁵ are independently hydrogen, a lower alkylgroup which optionally forms a heterocycloalkyl group with Y¹ ;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴ R⁵ taken together form a C₃ -C₆ heterocycloalkyl or a group of theformula: ##STR4## wherein e and f are independently 1, 2 or 3 and thesum of e and f is at least 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or C₁ -C₆ alkyl, or CH(C₀ -C₆ alkylene)-G³--R⁷ wherein G³ is CONH, CONH(C₁ -C₆ alkyl), NH, NH(C₁ -C₆ alkyl) and R⁷is hydrogen or C₁ -C₆ alkyl; or

CONH₂, CO[N(C₁ -C₆ alkyl)R⁸ ] wherein R⁸ is hydrogen or C₁ -C₆ alkyl;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

A² is hydrogen, C₁ -C₆ alkyl, (C₁ -C₆ alkylene)-G⁴ --R⁹ wherein G⁴ isoxygen or sulfur and R⁹ is hydrogen, trifluoromethyl or C₁ -C₆ alkyl;##STR5## wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl,or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- ordisubstituted with halogen, trifluoromethyl, amino, C₁ -C₆ alkyl, C₁ -C₆alkoxy, with the proviso that tetrazolyl can have at most onesubstituent;

Z¹ is C₁ -C₆ alkyl; and

V², Y² and A² are as defined above; ##STR6## where Z² is carbon ornitrogen;

where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R¹⁰ iscarboxamido, or (C₀ -C₆ alkylene)-G⁵ --R¹¹ wherein G⁵ is NH, NH(C₁ -C₆alkyl) and R¹¹ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula: ##STR7## wherein the N-ringrepresents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each ofwhich is optionally substituted with amino, trifluoromethyl,carboxamido, or (C₁ -C₆ alkylene)-G⁶ --R¹² wherein G⁶ is NH, NH(C₁ -C₆alkyl) and R¹² is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring.

The compounds of Formula I are antagonists at the CRF₁ receptor and areuseful in the diagnosis and treatment of stress related disorders suchas post traumatic stress disorder (PTSD) as well as depression, headacheand anxiety.

They are useful in methods for the treatment of psychiatric andaffective disorders and neurological diseases, including majordepression, headaches, anxiety-related disorders, post-traumatic stressdisorder, supranuclear palsy, as well as treatment of immunological,cardiovascular or heart-related diseases, hypertension, feedingdisorders, diabetes, dislipidemia, colonic hypersensitivity associatedwith psychopathological disturbance, and stress. Such methods involveadministration to a mammal of an effective amount of a compound of theinvention.

The compounds of Formula I are also neuropeptide Y₁ receptorantagonists, and, therefore, are also of value in the treatment of awide variety of clinical conditions which are characterized by thepresence of an excess of neuropeptide Y. The compounds of Formula I havedifferent chemical structures which affect their selectivity towardseither the CRF₁ or the NPY₁ receptors.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general Formula I: ##STR8## wherein Ar is phenyl, 1- or2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionallymono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy,amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkylcarboxamido, N,N-lower dialkyl carboxamido, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,with the proviso that at least one of the positions ortho or para to thepoint of attachment of Ar to the tricyclic ring system is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, C₁ -C₆ alkyl, or (C₁ -C₆alkyl)-G¹ --R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁ -C₆alkyl;

W is N or C--R³ where R³ is hydrogen or C₁ -C₆ alkyl; and

X is ##STR9## wherein V¹ and V² are CH₂, CO, CS, SO₂ or CH(C₁ -C₆alkyl), with the proviso that both V¹ and V² cannot both be CO, CS orSO₂ ;

Y¹ and Y² independently represent a bond or C₁ -C₆ alkylene;

A¹ is NR⁴ R⁵ wherein R⁴ and R⁵ are independently hydrogen, a lower alkylgroup which optionally forms a heterocycloalkyl group with Y¹ ;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴ R⁵ taken together form a C₃ -C₆ heterocycloalkyl or a group of theformula: ##STR10## wherein e and f are independently 1, 2 or 3 and thesum of e and f is at least 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or C₁ -C₆ alkyl, or CH(C₀ -C₆ alkylene)-G³--R⁷ wherein G³ is CONH, CONH(C₁ -C₆ alkyl), NH, NH(C₁ -C₆ alkyl) and R⁷is hydrogen or C₁ -C₆ alkyl; or

CONH₂, CO[N(C₁ -C₆ alkyl)R⁸ ] wherein R⁸ is hydrogen or C₁ -C₆ alkyl;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

A² is hydrogen, C₁ -C₆ alkyl, (C₁ -C₆ alkylene)-G⁴ --R⁹ wherein G⁴ isoxygen or sulfur and R⁹ is hydrogen, trifluoromethyl or C₁ -C₆ alkyl;##STR11## wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl,or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- ordisubstituted with halogen, trifluoromethyl, amino, C₁ -C₆ alkyl, C₁ -C₆alkoxy, with the proviso that tetrazolyl can have at most onesubstituent;

Z¹ is C₁ -C₆ alkyl; and

V², Y² and A² are as defined above; ##STR12## where Z² is carbon ornitrogen;

where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R¹⁰ iscarboxamido, or (C₀ -C₆ alkylene)-G⁵ --R¹¹ wherein G⁵ is NH, NH(C₁ -C₆alkyl) and R¹¹ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula: ##STR13## wherein the N-ringrepresents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each ofwhich is optionally substituted with amino, trifluoromethyl,carboxamido, or (C₁ -C₆ alkylene)-G⁶ --R¹² wherein G⁶ is NH, NH(C₁ -C₆alkyl) and R¹² is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring.

Preferred compounds of Formula I include those of Formula IA: ##STR14##wherein each R_(a) is C₁ -C₆ alkyl;

R_(b) is hydrogen or methyl;

R₁ is C₁ -C₆ alkyl;

R_(s) is C₁ -C₆ alkyl, (C₃ -C₅)cycloalkyl(C₁ -C₃)alkyl, (C₁-C₃)alkoxy(C₁ -C₃)alkyl, or (C₃ -C₅)cycloalkyl;

t is 1, 2 or 3; and

R_(x) is hydrogen, C₁ -C₆ alkyl, phenyl(C₁ -C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁ -C₆ alkyl, C₁-C₆ alkoxy, halogen, or hydroxy; and

R_(y) is hydrogen, C₁ -C₆ alkyl, (C₃ -C₆)cycloalkyl; or

NR_(x) R_(y) represents pyrrolidinyl, N-(C₁ -C₆)alkylpyrrolidin-2-yl,piperidinyl, morpholinyl, or N-(C₁ -C₆)alkylpiperazinyl.

Preferred compounds of Formula IA include those where R_(s) is C₁ -C₆alkyl or cyclopropylmethyl. Other preferred compounds of Formula IAinclude those where R_(s) is cyclopropyl(C₁ -C₃)alkyl. Still otherpreferred compounds of Formula IA include those where R_(x) and R_(y)independently represent hydrogen or C₁ -C₂ alkyl. More preferredcompounds of IA include those where R_(s) is cyclopropyl(C₁ -C₃)alkyl,R_(x) and R_(y) independently represent hydrogen or C₁ -C₂ alkyl; andeach R_(a) is methyl. Particularly preferred compounds of IA are those Wis nitrogen.

Other preferred compounds of Formula I include those of Formula IB:##STR15## wherein each R_(a) is C₁ -C₆ alkyl;

R₁ is C₁ -C₆ alkyl;

R_(s) is C₁ -C₆ alkyl, cyclopropyl(C₁ -C₃)alkyl or (C₁ -C₃)alkoxy(C₁-C₃)alkyl;

t is 1 or 2;

R_(x) is hydrogen, C₁ -C₆ alkyl, phenyl(C₁ -C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁ -C₆ alkyl, C₁-C₆ alkoxy, halogen, or hydroxy; and

R_(y) is hydrogen, C₁ -C₆ alkyl, (C₃ -C₆)cycloalkyl; or

NR_(x) R_(y) represents pyrrolidinyl, N-(C₁ -C₆)alkylpyrrolidin-2-yl,piperidinyl, morpholinyl, or N-(C₁ -C₆)alkylpiperazinyl.

Preferred compounds of Formula IB include those where R_(s) is C₁ -C₆alkyl or cyclopropylmethyl. Other preferred compounds of Formula IBinclude those where R_(s) is cyclopropyl(C₁ -C₃)alkyl. Yet otherpreferred compounds of Formula IB include those where t is 1 and R_(x)and R_(y) independently represent hydrogen or C₁ -C₂ alkyl. Morepreferred compounds of Formula IB include those where R_(s) iscyclopropyl(C₁ -C₃)alkyl, t is 1 and R_(x) and R_(y) independentlyrepresent hydrogen or C₁ -C₂ alkyl. Particularly preferred compounds ofIB are those where each R_(a) is methyl, R_(s) is cyclopropyl(C₁-C₃)alkyl, t is 1 and R_(x) and R_(y) independently represent hydrogenor C₁ -C₂ alkyl. Highly preferred compounds of Formula IB are thosewhere W is nitrogen.

Other preferred compounds of Formula I include those of Formula IC:##STR16## wherein each R_(a) is C₁ -C₆ alkyl;

R₁ is C₁ -C₆ alkyl;

t is 1 or 2;

R_(x) and R_(y) are different and represent hydrogen; (C₃-C₇)cycloalkylamino(C₁ -C₃)alkyl, carboxamido, (C₃ -C₇)cycloalkylamino,C₂ -C₆ alkanoyl optionally substituted in the ω-position with C₁ -C₆alkyl or phenyl optionally mono- or disubstituted independently with C₁-C₆ alkyl, C₁ -C₆ alkoxy, halogen, or hydroxy, provided that at leastone of R_(x) and R_(y) is hydrogen.

Preferred compounds of Formula IC include those wherein R¹ is C₁ -C₂alkyl and W is nitrogen. Other preferred compounds of IC are those whereeach R_(a) is methyl and W is nitrogen.

Other preferred compounds of the invention have Formula II ##STR17##wherein each R_(a) independently represents C₁ -C₆ alkyl;

R¹ is hydrogen, halogen, trifluoromethyl, C₁ -C₆ alkyl, or (C₁ -C₆alkyl)-G¹ --R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁ -C₆alkyl;

X is ##STR18## wherein V¹ and V² are CH₂, CO, CS, SO₂ or CH(C₁ -C₆alkyl), with the proviso that both V¹ and V² cannot both be CO, CS orSO₂ ;

Y¹ and Y² independently represent a bond or C₁ -C₆ alkylene;

A¹ is NR⁴ R⁵ wherein R⁴ and R⁵ are independently hydrogen, a lower alkylgroup which optionally forms a heterocycloalkyl group with Y¹ ;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴ R⁵ taken together form a C₃ -C₆ heterocycloalkyl or a group of theformula: ##STR19## wherein e and f are independently 1, 2 or 3 and thesum of e and f is at least 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or C₁ -C₆ alkyl, or CH(C₀ -C₆ alkylene)-G³--R⁷ wherein G³ is CONH, CONH(C₁ -C₆ alkyl), NH, NH(C₁ -C₆ alkyl) and R⁷is hydrogen or C₁ -C₆ alkyl; or

CONH₂, CO[N(C₁ -C₆ alkyl)R⁸ ] wherein R⁸ is hydrogen or C₁ -C₆ alkyl;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

A² is hydrogen, C₁ -C₆ alkyl, (C₁ -C₆ alkylene)-G⁴ --R⁹ wherein G⁴ isoxygen or sulfur and R⁹ is hydrogen, trifluoromethyl or C₁ -C₆ alkyl;##STR20## wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl,or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- ordisubstituted with halogen, trifluoromethyl, amino, C₁ -C₆ alkyl, C₁ -C₆alkoxy, with the proviso that tetrazolyl can have at most onesubstituent;

Z¹ is C₁ -C₆ alkyl; and

V², Y² and A² are as defined above; ##STR21## where Z² is carbon ornitrogen;

where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R¹⁰ iscarboxamido, or (C₀ -C₆ alkylene)-G⁵ --R¹¹ wherein G⁵ is NH, NH(C₁ -C₆alkyl) and R¹¹ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula: ##STR22## wherein the N-ringrepresents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each ofwhich is optionally substituted with amino, trifluoromethyl,carboxamido, or (C₁ -C₆ alkylene)-G⁶ --R¹² wherein G⁶ is NH, NH(C₁ -C₆alkyl) and R¹² is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring.

Preferred compounds of Formula II are those where V¹ and V² representmethylene; Y¹ is a bond; A¹ represents pyrrolidinyl, morpholinyl;piperazinyl, mono- or di-C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring; Y² represents a bond or methylene; and A²represents C₁ -C₆ alkyl or C₁ -C₆ alkoxymethyl.

Other preferred compounds of the invention have Formula III ##STR23##wherein each R_(a) independently represents C₁ -C₆ alkyl;

R¹ is hydrogen, halogen, trifluoromethyl, C₁ -C₆ alkyl, or (C₁ -C₆alkyl)-G¹ --R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁ -C₆alkyl; and

X is ##STR24## wherein V¹ and V² are CH₂, CO, CS, SO₂ or CH(C₁ -C₆alkyl), with the proviso that both V¹ and V² cannot both be CO, CS orSO₂ ;

Y¹ and Y² independently represent a bond or C₁ -C₆ alkylene;

A¹ is NR⁴ R⁵ wherein R⁴ and R⁵ are independently hydrogen, a lower alkylgroup which optionally forms a heterocycloalkyl group with Y¹ ;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴ R⁵ taken together form a C₃ -C₆ heterocycloalkyl or a group of theformula: ##STR25## wherein e and f are independently 1, 2 or 3 and thesum of e and f is at least 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or C₁ -C₆ alkyl, or CH(C₀ -C₆ alkylene)-G³--R⁷ wherein G³ is CONH, CONH(C₁ -C₆ alkyl), NH, NH(C₁ -C₆ alkyl) and R⁷is hydrogen or C₁ -C₆ alkyl; or

CONH₂, CO[N(C₁ -C₆ alkyl)R⁸ ] wherein R⁸ is hydrogen or C₁ -C₆ alkyl;

C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring;

A² is hydrogen, C₁ -C₆ alkyl, (C₁ -C₆ alkylene)-G⁴ --R⁹ wherein G⁴ isoxygen or sulfur and R⁹ is hydrogen, trifluoromethyl or C₁ -C₆ alkyl;##STR26## wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl,or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- ordisubstituted with halogen, trifluoromethyl, amino, C₁ -C₆ alkyl, C₁ -C₆alkoxy, with the proviso that tetrazolyl can have at most onesubstituent;

Z¹ is C₁ -C₆ alkyl; and

V², Y² and A² are as defined above; ##STR27## where Z² is carbon ornitrogen;

where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R¹⁰ iscarboxamido, or (C₀ -C₆ alkylene)-G⁵ --R¹¹ wherein G⁵ is NH, NH(C₁ -C₆alkyl) and R¹¹ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula: ##STR28## wherein the N-ringrepresents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each ofwhich is optionally substituted with amino, trifluoromethyl,carboxamido, or (C₁ -C₆ alkylene)-G⁶ --R¹² wherein G⁶ is NH, NH(C₁ -C₆alkyl) and R¹² is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring.

Preferred compounds of Formula III are those where V¹ and V² representmethylene; Y¹ is a bond; A¹ represents pyrrolidinyl, morpholinyl;piperazinyl, mono- or di-C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁ -C₆heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring; Y² represents a bond or methylene; and A²represents C₁ -C₆ alkyl or C₁ -C₆ alkoxymethyl.

Preferred compounds of the invention include:

4-(N-(2-N',N'-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N'-Ethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N'-Ethyl-N'-methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-methoxy-2-methylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Diethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N'-Methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Piperidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Piperidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N'-Ethyl-N'-methylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-(1-Imidazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-1-oxopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-2-(N'-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)-amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyridylmethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Aminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Aminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(3-Pyrrolidinopropyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-(2-Phenethylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Carboxamidoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N'-Ethyl-N'-methylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminooethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminooethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminooethyl)-N-cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-(1-Methyl-2-pyrrolidino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclobutyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

4-(N-(2-N',N'-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC--(CH₂)n--COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By "alkyl", "lower alkyl", or C₁ -C₆ alkyl in the present invention ismeant straight or branched chain alkyl groups having 1-6 carbon atomsoptionally forming a 3 to 6 atoms carbocycle, such as, for example,methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl,n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl, isopentyl,neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl,cyclohexyl.

By C₀ -C₆ alkylene is meant a direct bond or a C₁ -C₆ alkylene group,optionally forming a 3 to 6 atoms carbocycle, such as methylene,ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene,hexylidene, cyclohexylidene.

By "alkoxy", "lower alkoxy", or C₁ -C₆ alkoxy in the present inventionis meant straight or branched chain alkoxy groups having 1-6 carbonatoms optionally forming a 3 to 6 atoms carbocycle, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy,neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy,cyclohexoxy.

By "alkanoyl", "lower alkanoyl", or C₁ -C₆ alkanoyl as used herein ismeant straight or branched chain alkanoyl groups having 1-6 carbon atomsoptionally forming a 3 to 6 atom carbocycle, such as, for example,acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl, pentanoyl,cyclopentanoyl, hexanoyl, cyclhexanoyl. The "ω-position" of the alkanoylgroups herein is the terminal carbon atom.

CONH represents an amide functional group, i.e., ##STR29##

The term "heterocycle" or "heterocycloalkyl" means a monocyclic orbicyclic hydrocarbon group which in which one or more of the ring carbonatoms has been replaced with a heteroatom, e.g., oxygen, sulfur ornitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4heteroatoms.

By the term "halogen" in the present invention is meant fluorine,bromine, chlorine, and iodine.

Representative aminoalkyl substituted 9H-pyridino[2,3-b]indole and9H-pyrimidino[4,5-b]indole derivatives of the present invention, whichare encompassed by Formula I, include, but are not limited to thecompounds in Examples 1-18 and their pharmaceutically acceptableaddition salts.

The interaction of aminoalkyl substituted 9H-pyridino[2,3-b]indole and9H-pyrimidino[4,5-b]indole derivatives of the invention with CRF₁ andNPY₁ receptors is shown in the examples. This interaction results in thepharmacological activities of these compounds as illustrated in relevantanimal models.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachid oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachid oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 Umg to about 140 Umg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 Umg to about 7 Ug per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 Umg to about 500Umg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of Aminoalkyl Substituted 9H-Pyridino[2,3-b]indole and9H-Pyrimidino[4,5-b]indole Analogues

An illustration of the preparation of compounds of the present inventionis given in Scheme I, Scheme II and Scheme III. Those having skill inthe art will recognize that the starting materials may be varied andadditional steps employed to produce compounds encompassed by thepresent invention. ##STR30## wherein Ar, R¹ and R³ are as defined abovefor Formula I; and R¹⁴, R¹⁵ and R¹⁶ are encompassed by the definition ofX as defined in Formula I. ##STR31## wherein Ar, R¹ and R³ are asdefined above for Formula I; and R¹⁵ and R¹⁶ are encompassed by thedefinition of X as defined in Formula I. ##STR32## wherein Ar and R¹ areas defined as above for Formula I; and R¹⁵, R¹⁶ and R¹⁷ are encompassedby the definition of X as defined in Formula I.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

The preparation of the compounds of the present invention is illustratedfurther by the following Examples, which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

Commercial reagents were used without further purification. THF refersto tetrahydrofuran. LDA refers to lithium diisopropylamide and DDQrefers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Room or ambienttemperature refers to 20 to 25° C. Concentration implies the use of arotary evaporator. TLC refers to thin layer chromatography. Massspectral data were obtained either by CI or APCI methods.

EXAMPLE 1 A.2-Amino-4,5,6,7-tetrahydro-1-phenyl-1H-indole-3-carbonitrile ##STR33##

A mixture of 2,4,6-trimethylaniline (500 g) and adipoin (464 g) intoluene (2.5 L) is heated to reflux. A theoretical amount of water isremoved azeotropically over the course of 3 hours. The mixture is cooledto ambient temperature, then malononitrile (244 g) and ammonium acetate(57 g) are added. The reaction is slowly re-heated back to reflux forabout 1 hour with azeotropic removal of water. After cooling, theprecipitate that forms overnight is collected by filtration. The darksolid is washed with ethanol and dried to afford 540 g of a whitepowder: MS 280 (M+H).

B.4-Amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole##STR34##

To the product of Example 1A (535 g) dissolved in dichloroethane (4 L)are added 2-methoxypropene (550 mL) and p-toluenesulfonic acidmonohydrate (3.6 g). The mixture is refluxed for 1 hour then the solventis removed by distillation. The residue is dissolved in THF (3 L) andcooled to 0° C. To this solution, under an atmosphere of nitrogen gas,is added LDA (2.0M, 1.2 L) at a rate to keep the reaction's internaltemperature below 10° C. After 3 hours the reaction is neutralized withaqueous HCl. The aqueous layer is extracted with ethyl acetate andcombined with the THF layer. The combined organic phase is extractedwith 3M HCl and the latter is made alkaline (pH=10) with 10N NaOH andice. The aqueous solution is extracted with dichloromethane, dried withsodium sulfate, filtered and concentrated to give a crystalline solid:MS 320 (M+H).

C. 4-Amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR35##

The product of Example 1B (600 g) is dissolved in decahydronaphthalene(4 L) and heated to distill off low boiling impurities that are present.The solution is cooled to ambient temperature and charged with 10%Palladium on Carbon (250 g) under a blanket of argon gas. The mixture isheated to the reflux temperature of 191-193° C. for 9 hours to affordaromatized product. The cooled mixture is diluted with dichloromethaneand filtered through a pad of celite. The dichloromethane in thefiltrate is removed under reduced vacuum. The remainingdecahydronaphthalene solution is treated by bubbling in a stream ofhydrochloric acid gas with ice-cooling for about 5 minutes. The solidsare filtered, washed with diethyl ether and dried to yield 580 g ofproduct as the HCl salt. The salt is recrystallized from an ethylacetate and ethanol mixture to give a white product: MS(free base) 316(M+H).

D.4-(N-Cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR36##

A solution of dichloroethane (250 mL) containing the product of Example1C (50 g as HCl salt) and cyclopropanecarbonyl chloride (14 mL) atreflux is treated with dropwise addition of N,N-diisopropylethylamine(54 mL). After heating for 0.5 hour the reaction is cooled to ambienttemperature and poured into aqueous potassium carbonate solution. Theproduct is extracted with dichloromethane, dried over sodium sulfate,filtered and concentrated to give a white solid. This solid isre-dissolved in THF (600 mL) and mixed with borane-methyl sulfidecomplex (10M, 43 mL). The mixture is heated to reflux for 8 hours andquenched at room temperature with a large excess of methanol (about 200mL). Re-heat mixture to reflux for 1 hour, then concentrate underreduced pressure. More methanol (another 200 mL) is added to the gummyresidue and the solution is re-concentrated to yield a white solid: MS370 (M+H).

E.4-(N-(2-Chloroethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR37##

A solution containing the product from Example 1D (52 g) andchloroacetyl chloride (34 mL) in dichloroethane (500 mL) is refluxed for4 hours. The solvent and excess reagent are removed under reducedpressure. Aqueous potassium carbonate is added to the remaining oilyresidue and extracted with dichloromethane. The extract is dried withsodium sulfate, filtered and concentrated. The latter chloroacetylcompound (63 g) is dissolved in THF (250 mL). Add borane-methyl sulfidecomplex (10M, 14 mL) and stir at ambient temperature for 15 minutes thenfor 1 hour at reflux temperature. The solution is cooled back to roomtemperature, quenched with a large excess of methanol (100 mL) andre-heated to reflux for 1 hour. The solution is concentrated to give aviscous oil that crystallizes on standing: MS 432 (M+H).

F.4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 1) ##STR38##

A steel bomb containing the product from Example 1E (61 g), pyrrolidine(60 mL) and N-methylpyrrolidinone (250 mL) is sealed and heated to 120°C. for 5 hours. The mixture is poured into water and extracted withethyl acetate. The organic layer is washed with water, dried over sodiumsulfate, filtered and concentrated. The product is purified by flashchromatography. First 100% ethyl acetate is used to elute impuritiesfollowed by 10% methanol in dichloromethane to elute the desiredproduct. Obtain 60 g of compound that crystallizes on standing. Thesulfate salt of the amine is formed by adding concentrated sulfuric acid(2.44 mL) to amine (21.4 g) dissolved in ethanol (50 mL). Isopropanol(200 mL) is added to the ethanol solution at reflux. Crystals of sulfatethat form on cooling are collected by filtration and washed with coldisopropanol: MS(free base) 467 (M+H).

G.4-Propylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR39##

An excess of sodium borohydride (about 1 g) is added in small portionsto a propionic acid (10 mL) solution of the product from Example 1C (1.4g). After gas evolution ceases the reaction is heated to 100° C. for 0.5hour. Propionic acid is removed from the mixture under reduced pressureand crude product is extracted from aqueous potassium carbonate withdichloromethane. The dichloromethane extract is dried over sodiumsulfate, filtered and concentrated: MS 358 (M+H).

H.4-Cyclopropylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR40##

To a solution of the product from Example 1C (10 g) and 2-methoxypropene(50 mL) in dichloroethane (100 mL) is added acetic acid (1.6 mL) andsodium triacetoxyborohydride (25 g). The mixture is stirred at roomtemperature for 24 hours then concentrated. Dissolve residue in ethylacetate and wash with water, followed by 1N sodium hydroxide and brine.Dry over sodium sulfate, filter and concentrate: MS 358 (M+H).

EXAMPLE 2

The following compounds are prepared essentially according to theprocedures set forth above in Example 1.

a)4-(N-(2-N',N'-Dimethylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 429 (M+H). (Compound 2)

b)4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 445 (M+H). (Compound 3)

c)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 441 (M+H). (Compound 4)

d)4-(N-(2-N'-Ethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 441 (M+H). (Compound 5)

e)4-(N-(2-(N'-Ethyl-N'-methyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 6)

f)4-(N-2-(2-(S)-Methoxymethylpyrrolidino)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 511 (M+H). (Compound 7)

g)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-methoxy-2-methylphenyl)-9H-pyridino[2,3-b]indole:MS 443 (M+H). (Compound 8)

h)4-(N-(2-N',N'-Diethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 469 (M+H). (Compound 9)

i)4-(N-(2-N'-Methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 427 (M+H). (Compound 10)

j)4-(N-(2-Piperidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 481 (M+H). (Compound 11)

k)4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 12)

l)4-(N-(2-Piperidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 469 (M+H). (Compound 13)

m)4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 483 (M+H). (Compound 14)

n)4-(N-(2-N'-Ethyl-NI-methylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 443 (M+H). (Compound 15)

o)4-(N-(2-(1-Imidazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 464 (M+H). (Compound 16)

p)4-(N-2-(N'-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 496 (M+H). (Compound 17)

q)4-(N-2-(N'-Methylhomopiperazinyl)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 510 (M+H). (Compound 18)

r)4-(N-(2-N'-Isopropylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 454 (M+H). (Compound 19)

s)4-(N-(2-(2-(1-Methyl-2-pyrrolidino)ethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 524 (M+H). (Compound 20)

t)4-(N-(2-Piperazinylethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 482 (M+H). (Compound 21)

u)4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole:MS 453 (M+H). (Compound 22)

v)4-(N-(3-Pyrrolidinopropyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 481 (M+H). (Compound 23)

w)4-(N-(2-Methyl-2-pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS481 (M+H). (Compound 24)

x)4-(N-(4-Pyrrolidinobutyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 495 (M+H). (Compound 25)

y)4-(N-(2-(4-Piperidinopiperidinyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 564 (M+H). (Compound 26)

z)4-(N-(2-(2-Phenethylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 517 (M+H). (Compound 27)

aa)4-(N-(2-N'-Methylaminoethyl)-N-methyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 387 (M+H). (Compound 28)

bb)4-(N-(2-Pyrrolidinoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 471 (M+H). (Compound 29)

cc)4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 441 (M+H). (Compound 30)

dd)4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 469 (M+H). (Compound 31)

ee)4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 469 (M+H). (Compound 32)

ff)4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 443 (M+H). (Compound 33)

gg)4-(N-(2-(N'-Ethyl-NI-methyl)aminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 457 (M+H). (Compound 34)

hh)4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 35)

ii)4-(N-(2-N',N'-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 429 (M+H). (Compound 36)

jj)4-(N-(2-Guanidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 455 (M+H). (Compound 37)

kk)4-(N-(2-(2-(4-Methoxy)phenethylamino)ethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 521 (M+H). (Compound 38)

ll)4-(N-(2-N'-Cyclopentylaminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 39)

mm)4-(N-(2-N',N'-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 415 (M+H). (Compound 40)

nn)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphenyl)-9H-pyridino[2,3-b]indole:MS 427 (M+H). (Compound 41)

EXAMPLE 34-(N-(2-aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 42) ##STR41##

A solution of the product from Example 1E (900 mg) and sodium azide (410mg) in N-methylpyrrolidinone (10 mL) is heated to 120° C. for 2 hours.The mixture is poured into water and extracted with ethyl acetate. Theorganic layer is washed with water, dried over sodium sulfate, filteredand concentrated. An ethanol (10 mL) solution of the crude product and10% palladium on carbon (about 300 mg) is hydrogenated for 8 hours atapproximately 1 atmosphere pressure. The suspension is filtered overcelite and the concentrated product is purified by flash chromatography,then converted to the hydrochloride salt: MS(free base) 413 (M+H).(Compound 42)

The following compounds are prepared essentially according to theprocedure set forth in Example 3.

a)4-(N-(3-Aminopropyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 427 (M+H). (Compound 43)

b)4-(N-(2-Amino-2-methylethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 427 (M+H). (Compound 44)

c)4-(N-(2-Aminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 401 (M+H). (Compound 45)

d)4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole:MS 399 (M+H). (Compound 46)

e)4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphenyl)-9H-pyridino[2,3-b]indole:MS 399 (M+H). (Compound 47)

f)4-(N-(2-Aminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 387 (M+H). (Compound 48)

g)4-(N-(4-Aminobutyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 441 (M+H). (Compound 49)

EXAMPLE 44-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 50) ##STR42##

A solution containing the product from Example 3 (380 mg) in toluene (8mL) with N,N'-dimethylformamide azine (195 mg) and p-toluenesulfonicacid monohydrate (6 mg) is heated at reflux. A flowing stream ofnitrogen gas is used to displace evolving dimethylamine. After 12 hoursheating is discontinued and the solution is diluted with ethyl acetateand washed with water, brine and dried over sodium sulfate, filtered andconcentrated to a tan colored solid. The product is purified bypreparative TLC using 7% methanol and 0.1% ammonium hydroxide indichloromethane as eluent to afford 340 mg of product: MS 465 (M+H).

EXAMPLE 54-(N-(2-Carboxamidoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 51) ##STR43##

Dissolve the compound from Example 3 (1.0 g) and sodium cyanide (540 mg)in N-methylpyrrolidinone (20 mL) and heat to 95° C. for 2 hours. Themixture is poured into water and extracted with ethyl acetate. Theorganic layer is washed with water, dried over sodium sulfate, filteredand concentrated. Purify by flash chromatography using 20% ethyl acetatein hexanes to yield a white solid. Dissolve nitrile (130 mg) and solidsodium hydroxide (800 mg) in tert-butanol (5 mL). Reflux mixture forabout 1 hour. Next, neutralize with 6N hydrochloric acid, concentrateand purify residue by preparative TLC using 10% methanol indichloromethane as eluent: MS 441(M+H).

EXAMPLE 64-(N-(2-N'-acetyl-N'-methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 53) ##STR44##

To a solution of the compound from Example 2i (170 mg) indichloromethane (5 mL) is added acetic anhydride (0.1 mL) anddiisopropylethylamine (0.2 mL). The solution is stirred for 0.5 hourthen concentrated. The residue is dissolved in ethyl acetate, washedwith sodium carbonate and water, dried over sodium sulfate, filtered andconcentrated. The product is purified by preparative TLC using 70% ethylacetate in hexanes as eluent: MS 469 (M+H).

EXAMPLE 7

The following compounds are prepared essentially according to theprocedures set forth above in Example 6.

a)4-(N-(2-(N'-Methanesulfonyl-NI-methylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 505 (M+H). (Compound 54)

b)4-(N-(2-(N'-Methyl-N'-trifluoromethanesulfonyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 559 (M+H). (Compound 55)

c)4-(N-(2-(4-Aminophenylsulfonamido)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 568 (M+H). (Compound 56)

d)4-(N-(2-(2-Thienylsulfonamido)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 559 (M+H). (Compound 57)

e)4-(N-(2-(2-(2-Thienyl)-1-oxoethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 537 (M+H). (Compound 58)

f)4-(N-(2-(2-Phenyl-1-oxoethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 531 (M+H). (Compound 59)

EXAMPLE 84-(N-(2-N',N'-dimethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 60) ##STR45##

Refrigerated dimethylamine (about 4 mL) is poured into a solution of thechloroacetyl compound from Example 1E (1.9 g) and acetonitrile (20 mL).The reaction vessel is sealed and the mixture is stirred at ambienttemperature for 2 hours then concentrated. Water is added to the residueand the aqueous is extracted with ethyl acetate. The extract is driedover sodium sulfate, filtered and concentrated. The product is purifiedon preparative TLC with 100% ethyl acetate as the eluting solvent: MS443 (M+H).

EXAMPLE 9

The following compounds are prepared essentially according to theprocedure set forth in Example 8.

a)4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 443 (M+H). (Compound 61)

b)4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 459 (M+H). (Compound 62)

c)4-(N-(2-Pyrrolidino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 481 (M+H). (Compound 63)

d)4-(N-(2-N'-Ethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 64)

e)4-(N-(2-(N'-Ethyl-NI-methyl)amino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 469 (M+H). (Compound 65)

f)4-(N-(2-(2-(S)-Methoxymethylpyrrolidino)-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 525 (M+H). (Compound 66)

g)4-(N-(2-(1-Imidazolyl)-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 478 (M+H). (Compound 67)

EXAMPLE 10 A.4-(N-(2-Chloro-1-oxoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR46##

A solution of the compound from Example 1C (5.7 g), chloroacetylchloride (3 mL) and diisopropylethylamine (3 mL) in dichloroethane (90mL) is refluxed for 0.5 hour. After concentrating the mixture, aqueouspotassium carbonate is added and product is extracted withdichloromethane. The extract is dried over sodium sulfate, filtered andconcentrated. The chloride (1.0 g) is dissolved in acetonitrile (20 mL)and mixed with pyrrolidine (2 mL). The solution is stirred for 2 hoursat ambient temperature then concentrated. Water is added to the residueand the aqueous is extracted with ethyl acetate. The extract is driedover sodium sulfate, filtered and concentrated: MS 392 (M+H).

B.4-(N-(2-pyrrolidinoethyl)-N-1-oxopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 68) ##STR47##

To a solution of the compound from Example 10A (1.0 g) in acetonitrile(25 mL) is added pyrrolidine (1.0 mL). The solution is stirred at roomtemperature for 2 hours then concentrated. Water is added to the residueand the aqueous is extracted with ethyl acetate. The extract is driedover sodium sulfate, filtered and concentrated. The isolated aminoamide(1.1 g) is dissolved in THF (25 mL), treated with borane-methyl sulfidecomplex(10M, 1.0 mL) and refluxed for 8 hours. The solution is cooledand quenched with an excess of methanol (25 mL). Next,N,NI-dimethylethylenediamine (1.1 mL) is added and the mixture isre-heated to reflux for 4 hours. The solution is concentrated, dilutedwith ethyl acetate, washed with water, dried over sodium sulfate,filtered and concentrated. To a solution containing the latter product(330 mg), diisopropylethylamine (0.2 mL) and dichloroethane (10 mL) isadded propionyl chloride (0.1 mL). The mixture is refluxed for 0.5 hour,then poured into aqueous potassium carbonate and extracted with ethylacetate. The extract is dried over sodium sulfate, filtered andconcentrated. The product is purified on preparative TLC with 10%methanol in dichloromethane as the eluting solvent: 469 (M+H).

EXAMPLE 11

The following compounds are prepared essentially according to theprocedure set forth in Example 10.

a)4-(N-(2-Pyrrolidinoethyl)-N-cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 481 (M+H). (Compound 69)

b)4-(N-(2-Dimethylaminoethyl)-N-methoxymethyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 459 (M+H). (Compound 70)

EXAMPLE 124-(N-(2-pyridylmethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 71) ##STR48##

A solution of the compound from Example 1D (110 mg), picolinyl chloride(98 mg) and N,N-diisopropylethylamine in DMF (5 mL) is stirred at 60° C.for 12 hours. The mixture is poured into water and extracted with ethylacetate. The extract is washed with water, dried over sodium sulfate,filtered and concentrated. The product is purified by preparative TLCusing 30% ethyl acetate in hexanes as eluent: MS 461 (M+H).

EXAMPLE 13

The following compounds are prepared essentially according to theprocedure of Example 12.

a)4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 459 (M+H). (Compound 72)

b)4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 443 (M+H). (Compound 73)

c)4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-2-methoxy-1-oxoethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 473 (M+H). (Compound 74)

d)4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 455 (M+H). (Compound 75)

EXAMPLE 144-(4-Triazolyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound 76) ##STR49##

A solution containing the compound from Example 1C (560 mg) in toluene(10 mL) with N,NI-dimethylformamide azine (400 mg) and p-toluenesulfonicacid monohydrate (50 mg) is heated at reflux. A flowing stream ofnitrogen gas is used to displace evolving dimethylamine. After 24 hoursheating is discontinued and the solution is diluted with ethyl acetateand washed with water, brine and dried over sodium sulfate, filtered andconcentrated to a tan colored solid. The product is purified bypreparative TLC using 100% ethyl acetate as eluent to afford 340 mg ofproduct: MS 368 (M+H).

EXAMPLE 15 A.4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole##STR50##

Dissolve tert-butylnitrite (0.65 g) in acetonitrile (10 mL) and addcopper(II)chloride (0.68 g). Then the compound from Example 1C (1.33 g)is added portionwise to the greenish-brown solution and the mixture isstirred for 12 hours. The acetonitrile is removed by evaporation and theresidue is partitioned between water and dichloromethane. The aqueouslayer is extracted with more dichloromethane and the combined extract iswashed with water, dried over sodium sulfate, filtered and concentrated.The product is filtered through a plug of silica gel using 20% ethylacetate in hexanes as eluent to afford a tan colored solid: MS 335(M+H).

B.4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole(Compound77) ##STR51##

Combine the compound from Example 15A (200 mg) and piperazine (0.58 g)in N-methylpyrrolidinone (2 mL) and heat the solution to 120° C. for 12hours. Pour mixture into water and extract with ethyl acetate. Washextract with aqueous ammonium chloride then water. Dry extract oversodium sulfate, filter and concentrate. Purify by preparative TLC using10% methanol in dichloromethane as eluent: MS 385 (M+H).

EXAMPLE 16

The following compounds are prepared essentially according to theprocedures set forth above in Example 15.

a)4-(4-Methylpiperazinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 399 (M+H). (Compound 78)

b)4-Homopiperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 399 (M+H). (Compound 79)

c)4-(N-(2-(1Methyl-2-pyrrolidino)ethyl)-N-cyclopropylcarbonyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 495 (M+H). (Compound 80)

d)4-(N-2-(S)-Pyrrolidinomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 453 (M+H). (Compound 81)

e)4-(4-Aminomethylpiperidino)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 413 (M+H). (Compound 82)

f)4-(4-Piperidinopiperidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 467 (M+H). (Compound 83)

g)4-(4-Carboxamidopiperidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 427 (M+H). (Compound 84)

h)4-(3-Aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 385 (M+H). (Compound 85)

i)4-(N-(2-(1-Methyl-2-pyrrolidino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 481 (M+H). (Compound 86)

j)4-(N-2-(S)-Cyclopentylaminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 467 (M+H). (Compound 87)

k)4-(N-2-(R)-Cyclopentylaminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 467 (M+H). (Compound 88)

l)4-(N-3-Cyclopentylaminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 467 (M+H). (Compound 89)

m) 4-(N-3-(2-(3-Methoxy-4-ethoxy)phenethyl)aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 563 (M+H). (Compound 90)

n) 4-(N-3-(1-oxo-2-(3-Methoxy-4-ethoxy)phenethyl)aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 577 (M+H). (Compound 91)

o) 4-(N-2-(2-(R)-(4-Methoxy)phenethyl)aminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 533 (M+H). (Compound 92)

p) 4-(N-2-(2-(S)-(4-Methoxy)phenethyl)aminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 533 (M+H). (Compound 93)

q) 4-(N-4-(2-(3-Methoxy-4-ethoxy)phenethyl)aminomethylpiperazinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole:MS 563 (M+H). (Compound 94)

EXAMPLE 17 A. 2-Amino-1-phenyl-1H-indole-3-carbonitrile ##STR52##

Dissolve the compound from Example 1A (20 g) in 1,4-dioxane (300 mL) andadd DDQ (34 g) portionwise to the solution. The reaction is stirred for1 hour then filtered through celite to remove insoluble side products.The filtrate is concentrated and allowed to solidify. The product iscollected by filtration and washed with ethanol to yield 16 g of a tancolored powder: MS 276 (M+H).

B.4-Hydroxy-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole##STR53##

A mixture of the compound from Example 12A (30 g), acetic anhydride (15mL) and acetic acid (30 mL) is refluxed for 1 hour then, concentrated toa solid. Phosphoric acid (40 mL, 85%) is added to the amide. The mixtureis then refluxed for 0.5 hour and cooled to ambient temperature. Thesolution is poured onto ice and the precipitate that forms is collectedby filtration. The solids are washed with water and some ethanol: MS 318(M+H).

C.4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole##STR54##

The compound from Example 12B (2.2 g) is refluxed in phosphoryl chloride(30 mL) for 3 hours. The excess phosphoryl chloride is removed underreduced pressure and the residue is partitioned between aqueouspotassium carbonate and dichloromethane. The aqueous is extracted withmore dichloromethane. The combined extracts are dried over sodiumsulfate, filtered and concentrated to give a tan colored solid: MS 336(M+H).

D.4-Cyclopropylamino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole##STR55##

A mixture of the compound from Example 12C (750 mg) and cyclopropylamine(1.6 mL) in N-methylpyrrolidinone (2 mL) is heated to 65° C. in a sealedtube for 24 hours. Dilute mixture with ethyl acetate and wash withwater, brine, dry over sodium sulfate, filter and concentrate to give atan colored solid. Purify by radial chromatography using 40% ethylacetate in hexanes as eluent to give 730 mg of product: MS 357 (M+H).

E.4-(N-(2-N',N'-Dimethylaminooethyl)-N-cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole(Compound 95) ##STR56##

To a solution of compound from Example 12D (200 mg) in dimethylformamide(5 mL) at 0° C., under a blanket of nitrogen, is added sodium hydride(60%, 100 mg). After stirring the solution for 15 minutes,2-dimethylaminoethyl chloride hydrochloride (170 mg) is added. Themixture is then heated to 60° C. for 2 hours, then quenched with ice andwater. Diluted with ethyl acetate and washed with water, brine, driedover sodium sulfate, filtered and concentrated. Purified by radialchromatography using 7% methanol and 0.5% ammonium hydroxide indichloromethane as eluent to obtain 190 mg of product: MS 428 (M+H).

EXAMPLE 18

The following compounds are prepared essentially according to theprocedure of Example 17.

a)4-(N-(2-N',N'-Dimethylaminoethyl)-N-methyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 466 (M+H). (Compound 96)

b)4-(N-(2-N',N'-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 480 (M+H). (Compound 97)

c)4-(N-(2-N',N'-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(4-chloro-2-methylphenyl)-9H-pyrimidino[4,5-b]indole:MS 422 (M+H). (Compound 98)

d)4-(N-(2-Morpholinoethyl)-N-propyl)amino-2-methyl-9-(2-chloro-4-methylphenyl)-9H-pyrimidino[4,5-b]indole:MS 478 (M+H). (Compound 99)

e)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 442 (M+H). (Compound 100)

f)4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 386 (M+H). (Compound 101)

g)4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 468 (M+H). (Compound 102)

h)4-(3-Aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 386 (M+H). (Compound 103)

i)4-(2-(S)-Aminomethylpyrrolidino)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 400 (M+H). (Compound 104)

j)4-(3-Amino-2-triazolyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 384 (M+H). (Compound 105)

k)4-(3-Amino-1-triazolyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 384 (M+H). (Compound 106)

l)4-(3-Amino-4-triazolyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 384 (M+H). (Compound 107)

m)4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 532 (M+H). (Compound 108)

n)4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 456 (M+H). (Compound 109)

o)4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 470 (M+H). (Compound 110)

p)4-(N-(2-Pyrrolidinoethyl)-N-cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 454 (M+H). (Compound 111)

q)4-(N-(2-N',N'-Dimethylaminooethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 430 (M+H). (Compound 112)

r)4-(N-(2-N',N'-Dimethylaminoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 444 (M+H). (Compound 113)

s)4-(N-(2-Piperidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 470 (M+H). (Compound 114)

t)4-(N-(2-Piperidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 484 (M+H). (Compound 115)

u)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclobutyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 442 (M+H). (Compound 116)

v)4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopentyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 456 (M+H). (Compound 117)

w)4-(N-(2-N',N'-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 430 (M+H). (Compound 118)

x)4-(N-(2-N'-Methylaminoethyl)-N-methyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 388 (M+H). (Compound 119)

y)4-(4-(N-Methylamino)piperidino)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 414 (M+H). (Compound 120)

z)4-(4-(2-Aminoethyl)piperazinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 429 (M+H). (Compound 121)

aa)4-(N-(2-N'-Ethylaminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 416 (M+H). (Compound 122)

bb)(±)-4-(N-(2-N',N'-Dimethylaminoethyl)-N-1-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 444 (M+H). (Compound 123)

cc)4-(N-(2-N',N'-Diethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 470 (M+H). (Compound 124)

dd)4-(N-(2-N',N'-Diethylaminoethyl)-N-cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 456 (M+H). (Compound 125)

ee)4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 446 (M+H). (Compound 126)

ff)4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-ethoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 460 (M+H). (Compound 127)

gg)4-(N-(2-N'-Ethylaminoethyl)-N-ethyl)amino-2-methyl-9-(2-methyl-4-chlorophenyl)-9H-pyrimidino[4,5-b]indole:MS 423 (M+H). (Compound 128)

hh)4-(N-(Cyclopentylaminopiperidin-4-yl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 468 (M+H). (Compound 129)

ii)4-(N-(2-N',N'-Dimethylaminoethyl)-N-isobutyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 444 (M+H). (Compound 130)

jj)4-(N-(2-(3-Methoxy-4-ethoxy)phenethyl)aminopiperidin-4-yl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 578 (M+H). (Compound 131)

kk) 4-(N-(S)-(1-Oxo-2-(4-methoxy)phenethyl)aminopyrrolidin-2-yl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 54(M+H). (Compound 132)

ll) 4-(N-(S)-(2-(4-Methoxy)phenethyl)aminopyrrolidin-2-yl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole:MS 578 (M+H). (Compound 133)

EXAMPLE 19

The pharmaceutical utility of compounds of this invention is indicatedby the following assays for human CRF1 and NPY1 receptor activity.

Assay for CRF Receptor Binding Activity

CRF receptor binding is performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5,1991). Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EDTA andcentrifuged for 10 minutes at 48000 g. Membranes are washed again andbrought to a final concentration of 1500 mg/ml in binding buffer (Trisbuffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin).For the binding assay, 100 mL of the membrane preparation is added to 96well microtube plates containing 100 mL of ¹²⁵ I-CRF (SA 2200 Ci/mmol,final concentration of 100 pM) and 50 mL of drug. Binding is carried outat room temperature for 2 hours. Plates are then harvested on a Brandel96 well cell harvester and filters are counted for gamma emissions on aWallac 1205 Betaplate liquid scintillation counter. Non specific bindingis defined by 1 mM cold CRF. IC₅₀ values are calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.). The binding affinity for the compounds of Formula Iexpressed as IC₅₀ value, generally ranges from about 0.5 nanomolar toabout 10 micromolar.

Alternatively, the binding activity of the compounds of formula I to thehuman CRF₁ receptor can be measured as follows:

Assay for Human CRF Receptor Binding Activity in IMR32 cells

[¹²⁵ I]Sauvagine Binding to CRF1 Receptors Endogenously Expressed inIMR-32 Cells: IMR-32 human neuroblastoma cells are grown to 80%confluence in EMEM containing Earle's Balanced Salts and 2 mM1-glutamine with 10% FBS, 25 mM HEPES, 1 mM Sodium Pyruvate, andnonessential amino acids. At this time, flasks of cells are treated with2.5 μM 5-bromo-2'-deoxyuridine (Br-dU) for 10 days. Media is changedevery 3-4 days across the 10 day period. Cells are harvested usingNo-Zyme (JRH Biosciences) and rinsed with PBS. For membrane preparation,cells are homogenized in wash buffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mMEGTA, pH 7.4) and centrifuged at 48,000×g for 10 minutes at 4° C.Pellets are re-suspended, homogenized and centrifuged two additionaltimes. The receptor binding assay is performed using assay buffer (50 mMTris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin(22.0 mg/100 mL)), 150 μg protein/tube, and [¹²⁵ I]Sauvagine (NEN; 100pM for competition analysis and 10 pM-1 nM for saturation analysis) toyield a final volume of 200 μL. Nonspecific binding is defined using 2μM r/h CRF or 9-41 alpha-helical CRF. Cells are incubated for 2 hours atroom temperature. The assay is terminated by rapid vacuum filtration(Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI usingice-cold 50 mM Tris HCl and dry thoroughly by air. Specific Binding:70-80%; Kd (nM): 0.30 nM; Bmax (fmole/mg protein): 40-50. IC₅₀ valuesare calculated with the non-linear curve fitting program RS/1 (BBNSoftware Products Corp., Cambridge, Mass.).

The binding affinities for the compounds of Formula I towards the CRF₁receptor are expressed as IC₅₀ values and are less than 10 micromolar.

Assay for Human NPY1 Receptor Binding Activity

Compounds are assayed for activity using the following method:Baculovirus-infected Sf9 cells expressing recombinant human NPY Y1receptors are harvested at 42-48 hours at which time batches of 500 mLof cell suspension are pelleted by centrifugation. Each pellet isre-suspended in 30 mL of lysis buffer (10 mM HEPES, 250 mM sucrose, 0.5μg/mL leupeptin, 2 μg/mL Aprotonin, 200 μM PMSF and 2.5 mM EDTA, pH 7.4)and gently homogenized by 50 strokes using a dounce homogenizer. Thehomogenate is centrifuged at 4° C. for 10 minutes at 536×g to pellet thenuclei. The supernatant is collected into a fresh tube and centrifugedtwice in the same buffer at 48,000×g for 40 minutes. The final pellet issubsequently re-suspended in 10 mL of PBS containing 5 mM EDTA by douncehomogenization and stored in aliquots at -80° C.

Purified membranes are washed by PBS and re-suspended by gentlepipetting in binding buffer (50 mM Tris(HCl), 5 mM KCl, 120 mM NaCl, 2mM CaCl₂, 1 mM MgCl₂, 0.1% bovine serum albumin (BSA), pH 7.4).Membranes (5 μg) are added to siliconized (Sigmacote, Sigma)polypropylene tubes in addition to 0.050 nM [¹²⁵ I]NPY(porcine) forcompetition analysis or 0.010-0.500 nM [¹²⁵ I]NPY (porcine) forsaturation analysis. For evaluation of guanine nucleotide effects onreceptor affinity, GTP is added at a final concentration of 100 μM. Colddisplacers are added at concentrations ranging from 10⁻¹² M to 10⁻⁶ M toyield a final volume of 0.250 mL. Nonspecific binding is determined inthe presence of 1 μM NPY (human) and accounts for less than 10% of totalbinding. Following a 2 hour incubation at room temperature, the reactionis terminated by rapid vacuum filtration. Samples are filtered overpresoaked GF/C Whatman filters (1.0% polyethyleneimine for 2 hours) andrinsed 2 times with 5 mL cold binding buffer lacking BSA. Remainingbound radioactivity is measured by gamma counting. To estimate the Bmax,Kd and Ki, the results of binding experiments are analyzed usingSigmaPlot software (Jandel).

The binding affinities for the compounds of Formula I towards the NPY₁receptor are expressed as IC₅₀ values and are less than 10 micromolar.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR57## or thepharmaceutically acceptable salts thereof wherein whereinAr is phenyl,mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy,amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkylcarboxamido, N,N-lower dialkyl carboxamido, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,with the proviso that at least one of the positions ortho or para to thepoint of attachment of Ar to the tricyclic ring system is substituted;R¹ is hydrogen, halogen, trifluoromethyl, C₁ -C₆ alkyl, or (C₁ -C₆alkyl)-G¹ --R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁ -C₆alkyl; W is C--R³ where R³ is hydrogen or C₁ -C₆ alkyl; and X is##STR58## wherein V¹ and V² are CH₂, CO, CS, SO₂ or CH(C₁ -C₆ alkyl),with the proviso that both V¹ and V² cannot both be CO, CS or SO₂ ;Y¹and Y² independently represent a bond or C₁ -C₆ alkylene; A¹ is NR⁴ R⁵wherein R⁴ and R⁵ are independently Hydrogen or a lower alkyl group, orA¹ is C₁ -C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl,and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2-or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3-or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring, orlower alkanoyl, lower alkylsulfonyl, with theproviso that R⁴ and R⁵ cannot both be alkanoyl or alkylsulfonyl; or A¹is NR⁴ R⁵ wherein R⁴ is hydrogen or a C₁ -C₆ alkyl group and R⁵ forms aheterocycloalkyl group with Y¹ when Y¹ is alkylene; or A¹ is NR⁴ R⁵wherein NR⁴ R⁵ is a C₃ -C₆ heterocycloalkyl, or A¹ is NR⁴ R⁵ wherein NR⁴R⁵ is a 5- or 6-membered nitrogen heterocycle optionally containing anoxygen or second nitrogen atom, or A¹ is a group of the formula:##STR59## wherein e and f are independently 1, 2 or 3 and the sum of eand f is at least 3; and G² isNR⁶ wherein R⁶ is hydrogen or C₁ -C₆alkyl, or CH(C₀ -C₆ alkylene)-G³ --R⁷ wherein G³ is CONH, CONH(C₁ -C₆alkyl), NH, NH(C₁ -C₆ alkyl) and R⁷ is hydrogen or C₁ -C₆ alkyl; orCONH₂, CO[N(C₁ -C₆ alkyl)R⁸ ] wherein R⁸ is hydrogen or C₁ -C₆ alkyl; C₁-C₆ arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring; A² is hydrogen, C₁ -C₆ alkyl, (C₁-C₆ alkylene)-G⁴ --R⁹ wherein G⁴ is oxygen or sulfur and R⁹ is hydrogen,trifluoromethyl or C₁ -C₆ alkyl; ##STR60## wherein heteroaryl is 1-, 2-or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3-or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- or disubstituted withhalogen, trifluoromethyl, amino, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, with theproviso that tetrazolyl can have at most one substituent;Z¹ is C₁ -C₆alkyl; and V², Y² and A² are as defined above; ##STR61## where Z² iscarbon or nitrogen; wherewhen Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2,or 3, R is carboxamido, or (C₀ -C₆ alkylene)-G -R wherein G5 is NH,NH(C₁ -C₆ alkyl) and R is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ arylalkyl or C₁-C₆ heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which isoptionally mono-, di-, or tri-substituted with halogen, trifluoromethyl,hydroxy, amino, lower alkylamino, lower dialkylamino, loweralkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2adjacent substituents can together form a 5-7 fused cycloalkyl orheterocycloalkyl ring; when Z is carbon, n is 1 or 2 and p is 1 or 2,R¹⁰ is amino; or when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰is hydrogen; or (iv) a nitrogen heterocycle of the formula: ##STR62##wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, orpyrazolyl, each of which is optionally substituted with amino,trifluoromethyl, carboxamido, or (C₁ -C₆ alkylene)-G⁶ --R¹² wherein G⁶is NH, NH(C₁ -C₆ alkyl) and R¹² is hydrogen, C₁ -C₆ alkyl, C₁ -C₆arylalkyl or C₁ -C₆ heteroarylalkyl, where aryl is phenyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, or 5-pyrimidinyl, 1-, 2- or4-imidazolyl, 2-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono-, di-, or tri-substitutedwith halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lowerdialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, withthe proviso that 2 adjacent substituents can together form a 5-7 fusedcycloalkyl or heterocycloalkyl ring.
 2. A compound according to claim 1,where W is CH, Ar is 2,4,6-trimethylphenyl, R₁ is methyl, and X isN-(2-aminoethyl)-N-(cyclopropylmethyl),N-(2-pyrrolidinoethyl)-N-(cyclopropylmethyl),N-(2-N',N'-dimethylaminoethyl)-N-(propyl),N-(2-(N',N'-dimethyl)aminoethyl)-N-(2-methoxyethyl),N-(2-(N',N'-dimethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-(N'-ethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-(N'-methyl-N'-ethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-(N',N'-diethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-(N'-methyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-piperidinoethyl)-N-(cyclopropylmethyl),N-(2-pyrrolidinoethyl)-N-(propyl), N-(2-piperidinoethyl)-N-(propyl),N-(2-morpholinoethyl)-N-(cyclopropylmethyl),N-(2-(N'-methyl-N'-ethyl)aminoethyl)-N-(propyl),N-(2-(N'-methyl)piperazinyl)-N-(cyclopropylmethyl),N-(2-(N'-methyl)homopiperazinyl)-N-(cyclopropylmethyl),N-(2-(N'-isopropyl)aminoethyl)-N-(cyclopropylmethyl),N-(3-aminopropyl)-N-(cyclopropylmethyl), N-(2-aminoethyl)-N-(propyl),N-(2-aminoethyl)-N-(ethyl),N-(3-pyrrolidinopropyl)-N-(cyclopropylmethyl),N-(4-pyrrolidinobutyl)-N-(cyclopropylmethyl),N-(2-(N'-2-phenethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-pyrrolidinoethyl)-N-(2-methoxyethyl),N-(2-pyrrolidinoethyl)-N-(ethyl), N-(2-pyrrolidinoethyl)-N-(butyl),N-(2-pyrrolidinoethyl)-N-(isopropyl),N-(2-(N',N'-dimethyl)aminoethyl)-N-(isobutyl),N-(2-(N'-methyl-N'-ethyl)aminoethyl)-N-(isobutyl),N-(2-(N'-methylpyrrolidin-2-yl)ethyl)-N-(cyclopropylmethyl),N-(2-pyrrolidinoethyl)-N-(isopropyl),N-(2-(N',N'-dimethyl)aminoethyl)-N-(isopropyl),N-(2-(N'-cyclopentyl)aminoethyl)-N-(ethyl),N-(2-(N'-2-(4-methoxy)phenethyl)aminoethyl)-N-(ethyl),N-((1-methyl-2-pyrrolidino)ethyl)-N-(cyclopropylmethyl),N-((1-methyl-2-amino)ethyl)-N-(cyclopropylmethyl).
 3. A compoundaccording to claim 1, where W is CH, Ar is 2,4,6-trimethylphenyl, R₁ ismethyl, and X is N-(1-oxo-2-(N',N'-dimethyl)aminoethyl)-N-(propyl),N-(2-oxo-2-(N',N'-dimethyl)aminoethyl)-N-(propyl),N-(1-oxo-2-(N',N'-dimethyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-pyrrolidinoethyl)-N-(1-oxo-propyl),N-(2-pyrrolidinoethyl)-N-(1-oxo-cyclopropyl),N-(2-oxo-2-(N',N'-dimethyl)aminoethyl)-N-(cyclopropyl).
 4. A compoundaccording to claim 1, where W is CH, Ar is 2,4,6-trimethylphenyl, R₁ ismethyl, and X is 2-(S)-(cyclopentylaminomethyl)pyrrolidinyl,4-(carboxamido)piperidinyl, 3-(cyclopentylamino)pyrrolidinyl,3-(1-oxo-2-((3-methoxy-4-ethoxy)phenyl)aminoethyl)pyrrolidinyl,2-(2-(4-methoxy)phenyl)aminoethyl)pyrrolidinyl,3-(1-oxo-2-((3-methoxy-4-ethoxy)phenyl)ethyl)pyrrolidinyl,4-(2-((3-methoxy-4-ethoxy)phenyl)aminoethyl)piperidinyl.
 5. A compoundaccording to claim 1, where W is CH, Ar is 2-methyl-4-methoxy phenyl, R₁is methyl, and X isN-(2-(N',N'-dimethyl)aminoethyl)-N-(cyclopropylmethyl).
 6. A compoundaccording to claim 1, where W is CH, Ar is 2,4-dimethylphenyl, R₁ ismethyl, and X is N-(2-pyrrolidinoethyl)-N-(cyclopropylmethyl).
 7. Acompound according to claim 1, where W is CH, Ar is 2,6-dimethylphenyl,R₁ is methyl, and X isN-(2-(N',N'-dimethyl)aminoethyl)-N-(cyclopropylmethyl).
 8. A compoundaccording to claim 1, where W is CH, Ar is 2,4,6-trimethylphenyl, R₁ ismethyl, and X is N-(2-(1-imidazolyl)aminoethyl)-N-(cyclopropylmethyl),N-(2-(1,2,4-triazol-4-yl)aminoethyl)-N-(cyclopropylmethyl).
 9. Acompound of the formula: ##STR63## wherein W is C--R³ where R³ ishydrogen or C₁ -C₆ alkyl:each R_(a) is the same or different and is C₁-C₆ alkyl; R_(b) is hydrogen or methyl; R₁ is C₁ -C₆ alkyl; R_(s) is C₁-C₆ alkyl, (C₃ -C₅)cycloalkyl(C₁ -C₃)alkyl, (C₁ -C₃)alkoxy(C₁ -C₃)alkyl,or (C₃ -C₅)cycloalkyl; t is 1, 2 or 3; and R_(x) is hydrogen, C₁ -C₆alkyl, phenyl(C₁ -C₆)alkyl where phenyl is optionally mono- ordisubstituted independently with C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halogen,or hydroxy; and R_(y) is hydrogen, C₁ -C₆ alkyl, (C₃ -C₆)cycloalkyl; orNR_(x) R_(y) represents pyrrolidinyl, N-(C₁ -C₆)alkylpyrrolidin-2-yl,piperidinyl, morpholinyl, or N-(C₁ -C₆)alkylpiperazinyl.
 10. A compoundaccording to claim 9, wherein R_(s) is C₁ -C₆ alkyl orcyclopropylmethyl.
 11. A compound according to claim 10, wherein R_(s)is cyclopropyl(C₁ -C₃)alkyl.
 12. A compound according to claim 11,wherein R_(x) and R_(y) independently represent hydrogen or C₁ -C₂alkyl.
 13. A compound according to claim 12, wherein each R_(a) ismethyl.
 14. A compound of the formula: ##STR64## wherein W is C--R³where R³ is hydrogen or C₁ -C₆ alkyl;each R_(a) is the same or differentand is C₁ -C₆ alkyl; R₁ is C₁ -C₆ alkyl; R_(s) is C₁ -C₆ alkyl,cyclopropyl(C₁ -C₃)alkyl or (C₁ -C₃)alkoxy(C₁ -C₃)alkyl; t is 1 or 2;R_(x) is hydrogen, C₁ -C₆ alkyl, phenyl(C₁ -C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁ -C₆ alkyl, C₁-C₆ alkoxy, halogen, or hydroxy; and R_(y) is hydrogen, C₁ -C₆ alkyl,(C₃ -C₆)cycloalkyl; or NR_(x) R_(y) represents pyrrolidinyl, N-(C₁-C₆)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N-(C₁-C₆)alkylpiperazinyl.
 15. A compound according to claim 14, whereinR_(s) is C₁ -C₆ alkyl or cyclopropylmethyl.
 16. A compound according toclaim 15, wherein R_(s) is cyclopropyl(C₁ -C₃)alkyl.
 17. A compoundaccording to claim 16, wherein t is 1 and R_(x) and R_(y) independentlyrepresent hydrogen or C₁ -C₂ alkyl.
 18. A compound according to claim17, wherein each R_(a) is methyl.
 19. A compound of the formula:##STR65## wherein W is C--R³ where R³ is hydrogen or C₁ -C₆ alkyl;eachR_(a) may be the same or different and is C₁ -C₆ alkyl; R₁ is C₁ -C₆alkyl; t is 1 or 2; R_(p) and R_(q) are different and representhydrogen; (C₃ -C₇)cycloalkylamino(C₁ -C₃)alkyl, carboxamido, (C₃-C₇)cycloalkylamino, C₂ -C₆ alkanoyl optionally substituted in theω-position with C₁ -C₆ alkyl, or phenyl optionally mono- ordisubstituted independently with C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halogen,or hydroxy, provided that at least one of R_(p) and R_(q) is hydrogen.20. A compound according to claim 19, wherein each R_(a) is methyl. 21.A compound according to claim 1 whichis4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N'-Ethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(N'-Ethyl-N'-methyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(2-(S)-Methoxymethylpyrrolidino)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-methoxy-2-methylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Diethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-N'-Methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.22. A compound according to claim 1 whichis4-(N-(2-Piperidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Piperidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N'-Ethyl-NI-methylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(1-Imidazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(N'-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(N'-Methylhomopiperazinyl)ethyl-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N'-Isopropylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-(1-Methyl-2-pyrrolidino)ethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-Piperazinylethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.23. A compound according to claim 1 whichis4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(3-Pyrrolidinopropyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Methyl-2-pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(4-Pyrrolidinobutyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(4-Piperidinopiperidinyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-Phenethylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N'-Methylaminoethyl)-N-methyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.24. A compound according to claim 1 whichis4-(N-(2-N',N'-Dimethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(N'-Ethyl-NI-methyl)aminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Guanidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole;4-(N-(2-(2-(4-Methoxy)phenethylamino)ethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N'-Cyclopentylaminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.25. A compound according to claim 1 whichis4-(N-(3-Aminopropyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Amino-2-methylethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Aminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Aminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(4-Aminobutyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Carboxamidoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-N'-acetyl-N'-methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.26. A compound according to claim 1 whichis4-(N-(2-(N'-Methanesulfonyl-N'-methylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(N'-Methyl-N'-trifluoromethanesulfonyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(4-Aminophenylsulfonamido)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-Thienylsulfonamido)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-(2-Thienyl)-1-oxoethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-Phenyl-1-oxoethyl)aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-dimethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-Pyrrolidino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.27. A compound according to claim 1 whichis4-(N-(2-N'-Ethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(N'-Ethyl-NI-methyl)amino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(2-(S)-Methoxymethylpyrrolidino)-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(1-Imidazolyl)-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-pyrrolidinoethyl)-N-1-oxopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Pyrrolidinoethyl)-N-cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-Dimethylaminoethyl)-N-methoxymethyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-pyridylmethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylamino-2-oxoethyl)-N-2-methoxy-1-oxoethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-N',N'-Dimethylamino-1-oxoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(4-Triazolyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(4-Methylpiperazinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-Homopiperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-(2-(1-Methyl-2-pyrrolidino)ethyl)-N-cyclopropylcarbonyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(S)-Pyrrolidinomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(4-Aminomethylpiperidino)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(4-Piperidinopiperidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(4-Carboxamidopiperidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(3-Aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.28. A compound according to claim 1 whichis4-(N-(2-(1-Methyl-2-pyrrolidino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(S)-Cyclopentylaminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(R)-Cyclopentylaminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-3-Cyclopentylaminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-3-(2-(3-Methoxy-4-ethoxy)phenethyl)aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-3-(1-oxo-2-(3-Methoxy-4-ethoxy)phenethyl)aminopyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(2-(R)-(4-Methoxy)phenethyl)aminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;4-(N-2-(2-(S)-(4-Methoxy)phenethyl)aminomethylpyrrolidinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole;or4-(N-4-(2-(3-Methoxy-4-ethoxy)phenethyl)aminomethylpiperazinyl)-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole.29. A method of treating, anxiety, depression, post-traumatic stressdisorder, inflammatory diseases, obesity, in mammals,comprising:administering to the mammal a therapeutically effectiveamount of a compound of claim
 1. 30. A pharmaceutical compositioncomprising a compound according to claim 1 together with at least onepharmaceutically acceptable carrier or excipient.
 31. A method oftreating hypertension in mammals, comprising administering to the mammala therapeutically effective amount of a compound of claim
 1. 32. Amethod of suppressing appetite in mammals, comprising administering tothe mammal a therapeutically effective amount of a compound of claim 1.